Clinical and Experimental Pharmacology and Physiology (2009) 36, 425– 435 doi: 10.1111/j.1440-1681.2008.05077.x Blackwell Publishing Asia Tryptophan metabolism and depression GM Mackay et al. KYNURENINE METABOLITES AND INFLAMMATION MARKERS IN DEPRESSED PATIENTS TREATED WITH FLUOXETINE OR COUNSELLING Gillian M Mackay,* Caroline M Forrest,* John Christofides, † Michala A Bridel, † Susan Mitchell, ‡ Richard Cowlard, § Trevor W Stone* and L Gail Darlington ¶ *Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, ‡ Fitznells Manor, Ewell, † Chemical Pathology, West Park Hospital, § The Old Cottage Hospital Surgery and ¶ Epsom General Hospital, Epsom, UK SUMMARY 1. Depression could result from changes in tryptophan availability caused by activation of the kynurenine pathway as a result of inflammation. In the present study, we examined patients newly diagnosed with depression to determine whether kynurenines and related factors change in parallel with improvements in mood. 2. Concentrations of 5-hydroxytryptamine (5-HT; serotonin), 5-hydroxyindoleacetic acid (5-HIAA), oxidized tryptophan metabolites, brain-derived neurotrophic factor (BDNF) and inflammatory mediators (interleukin (IL)-2, C-reactive protein (CRP), neopterin) were measured in peripheral blood during an 18 week period of treatment with fluoxetine, fluoxetine plus tri-iodothyronine (T 3 ) or psychiatric counselling. 3. The results showed significant improvements in mood, with reduced 5-HT concentrations in patients given fluoxetine and a rise in plasma tryptophan in patients given counselling or fluoxetine and T 3 . The addition of T 3 to the fluoxetine regimen appeared to slow recovery from depression, although the use of T 3 was associated with a fall in thyroxine concentrations. Changes in 5-HT concentrations did not correlate with psychiatric scores and were seen only in drug-treated groups, not those given counselling. There were no associated changes in absolute concentrations of kynurenines, BDNF, CRP, neopterin or IL-2. With fluoxetine treatment, there were correlations between the concentrations of kynurenine metabolites and the psychiatric rating scores, whereas no correlations were found with BDNF or inflammatory markers. 4. It is concluded that depression scores are largely independent of inflammatory status, but kynurenine metabolism may be related to the degree of depression after fluoxetine treatment. Key words: brain-derived neurotrophic factor, depression, 5-hydroxytryptamine, inflammation, kynurenine, serotonin, tryptophan. INTRODUCTION The neurochemical basis of major depression remains unclear. The earliest hypotheses, based on a simplistic concept of the need to achieve critical brain concentrations of monoamines, such as noradrenaline and 5-hydroxytryptamine (5-HT), to maintain synaptic transmission, have evolved into more sophisticated views based on changes in receptor function. 1 Some of the receptor changes may be secondary to chronic changes in 5-HT concentrations, 2 but analyses of nucleotide polymorphisms also suggest a strong link between some aspect of 5-HT metabolism, especially of the serotonin transporter, and the extent of depression or its response to drug treatment. 3,4 Despite this continuing interest in 5-HT, recent years have seen the development of alternative views on the aetiology of depression. There is good evidence for a role of neuronal growth factors, especially brain-derived neurotrophic factor (BDNF), 1 which itself may have indirect actions on the 5-HT transporter or receptors. 5 There is also growing interest in the role of an underlying inflammatory state in depression, as reflected by changes in the concentrations of neopterin or cytokines in patients experiencing depression either endogenously or as a result of treatment with cytokines and interferons. 6 One neurochemical pathway that bridges the 5-HT and inflammatory hypotheses is the kynurenine pathway of tryptophan metabolism. This pathway involves the sequential oxidative metabolism of tryptophan through l-kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid, with the additional generation of kynurenic acid and picolinic acid. 7,8 There are two variants of the pathway initiated by the selective enzyme tryptophan-2,3-dioxygenase (TDO) or the more non-specific indoleamine-2,3-dioxygenase (IDO). The latter occurs widely in many tissues, including monocytes and macrophages, in which it is activated by inflammatory mediators such as interferon- and bacterial lipopolysaccharides. 9,10 The existence of inflammation activates IDO, enhancing the conversion of tryptophan to kynurenines and lowering the concentration of tryptophan available for the synthesis of 5-HT. Therefore, inflammation could lead indirectly to a depletion of brain 5-HT via activation of the kynurenine pathway, resulting in the development of depression. 11 Such a mechanism would explain why depression is believed to be a primary symptom of inflammatory conditions such as rheumatoid arthritis and not a secondary response to the presence of the inflammation. In the present study, we examined, in patients, concentrations of 5-HT, its major metabolite 5-hydroxy-indoleacetic acid (5-HIAA), tryptophan, its oxidized kynurenine metabolites and inflammatory markers, such as neopterin and interleukin (IL)-2. We also examined Correspondence: Professor TW Stone, West Medical Building, University of Glasgow, Glasgow G12 8QQ, UK. Email: t.w.stone@bio.gla.ac.uk All authors declare that they have no potential conflicts of interest relating to the data presented in this report or its publication. Received 26 June 2008; revision 22 August 2008; accepted 28 August 2008. © 2008 The Authors Journal compilation © 2008 Blackwell Publishing Asia Pty Ltd